A PK/PD Approach to Antibiotic Therapy

Introduction

Pharmacokinetics (PK) is concerned with the time course of antimicrobial concentrations in the body, while pharmacodyamics (PD) is concerned with the relationship between those concentrations and the antimicrobial effect. Antibiotic dosing regimens have traditionally been determined by PK parameters only. However, PD plays an equal, if not more important, role. In this age of increasing antimicrobial resistance, PD becomes even more important because these parameters may be used to design dosing regimens which counteract or prevent resistance.

Discussion

The primary measure of antibiotic activity is the minimum inhibitory concentration (MIC). The MIC is the lowest concentration of an antibiotic that completely inhibits the growth of a microorganism in vitro. While the MIC is a good indicator of the potency of an antibiotic, it indicates nothing about the time course of antimicrobial activity.

PK parameters quantify the serum level time course of an antibiotic. The three pharmacokinetic parameters that are most important for evaluating antibiotic efficacy are the peak serum level (Cmax), the trough level (Cmin), and the Area Under the serum concentration time Curve (AUC). While these parameters quantify the serum level time course, they do not describe the killing activity of an antibiotic.

Integrating the PK parameters with the MIC gives us three PK/PD parameters which quantify the activity of an antibiotic: the Peak/MIC ratio, the T>MIC, and the 24h-AUC/MIC ratio. The Peak/MIC ratio is simply the Cpmax divided by the MIC. The T>MIC (time above MIC) is the percentage of a dosage interval in which the serum level exceeds the MIC. The 24h-AUC/MIC ratio is determined by dividing the 24-hour-AUC by the MIC.

Antimicrobial Patterns

The three pharmacodyamic properties of antibiotics that best describe killing activity are time-dependence, concentration-dependence, and persistent effects. The rate of killing is determined by either the length of time necessary to kill (time-dependent), or the effect of increasing concentrations (concentration-dependent). Persistent effects include the Post-Antibiotic Effect (PAE). PAE is the persistant suppression of bacterial growth following antibiotic exposure.

For Type I antibiotics (AG's, fluoroquinolones, daptomycin and the ketolides), the ideal dosing regimen would maximize concentration,
because the higher the concentration, the more extensive and the faster is the degree of killing. Therefore, the Peak/MIC ratio is the important
predictors of antibiotic efficacy. For aminoglycosides, it is best to have a Peak/MIC ratio of at least 8-10 to prevent resistence.

Type II antibiotics (beta-lactams, clindamycin, erythromcyin, and linezolid) demonstrate the complete opposite properties. The ideal dosing
regimen for these antibiotics maximizes the duration of exposure. The T>MIC is the parameter that best correlates with efficacy. For
beta-lactams and erythromycin, maximum killing is seen when the time above MIC is at least 70% of the dosing interval.

Type III antibiotics (vancomycin, tetracyclines, azithromycin, and the dalfopristin-quinupristin combination) have mixed properties, they have
time-dependent killing and moderate persistent effects. The ideal dosing regimen for these antibiotics maximizes the amount of drug received.
Therefore, the 24h-AUC/MIC ratio is the parameter that correlates with efficacy. For vancomycin, a 24h-AUC/MIC ratio of at least 400 is necessary for MRSA.

Outcome studies

Aminoglycoside Pharmacodynamics in Vivo

Initial serum peak level

Died

Survived

< 5mcg/ml

21%

79%

>= 5mcg/ml

2%

98%

Moore et al, J Infect Dis 149: 443, 1984

Aminoglycoside Pharmacodynamics in vivo

Moore et al, J Infect Dis 155: 93, 1987

Vancomycin Outcome vs 24h-AUC/MIC ratio

An early study by Hyatt et al, found:

24h-AUC/MIC ratio

Satisfactory

Unsatisfactory

< 125

4 (50%)

4

> 125

71 (97%)

2

A 2012 study by Brown et al found that patients with an AUC24/MIC ratio of less than 211 had a greater that 4-fold increase in attributable mortality
than patients who received vancomycin doses that achieved an AUC24/MIC ratio of greater than 211.

A 2016 meta-analysis by Men et al, demonstrated that achieving a high 24-hr AUC/MIC of vancomycin significantly decreases mortality rates by 53%
and rates of infection treatment failure by 61%, with 400 being a reasonable target.

Fluoroquinolone Pharmacodynamics vs S. pneumoniae

24h-AUC/MIC ratio

Microbiological Response

< 33.7

(64%)

> 33.7

(100%)

Ambrose et al, Antimicrob Agents Chemo 10: 2793, 2001

Pharmacodynamics of Beta-Lactams and Macrolides in Otitis Media

Craig et al, Ped Infect Dis 15: 255, 1996

Conclusion

PK dosing has shown us that one dose is not appropriate for all patients. Pharmacodynamics shows us that one target level is not appropriate for all patients. We need to evalaute both the serum level data and the MIC, taking into consideration the PD properties of the drug.